1. Field of Invention
The present invention relates to the preparation of 3,5-Dimethoxy-4′-O-tetrahydropyranylstilbene, which is a key intermediate for the synthesis of Stilbenes such as Pterostilbene and Resveratrol. The present invention also relates to new crystalline compounds of Pterostilbene, more particularly, the invention relates to Pterostilbene polymorphs, therapeutic uses of those Pterostilbene polymorphs, and pharmaceutical/nutraceuticals compositions containing them.
2. Description of the Related Art
Pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) is a naturally occurring stilbenoid compound that is a structural analog of Resveratrol. The chemical structures of Pterostilbene and Resveratrol are:

Methods for preparing stilbenes such as Pterostilbene and Resveratrol are known in the art. JMC, 2002, 45 (12), 2534-2542 discloses a process for preparing Pterostilbene by: condensing 3,5-Dimethoxybenzyltriphenylphosphonium bromide with 4-(tert-butyldimethylsilyloxy)benzaldehyde in tetrahydrofuran yields 4′-(tert-butyldimethyl silyloxy)-3,5-dimethoxystilbene; and treating 4′-(tert-Butyldimethylsilyloxy)-3,5-dimethoxystilbene with tetrabutyl ammonium fluoride affords Pterostilbene.
CN 1948274 discloses a process for preparing Pterostilbene by: condensing 4-benzyloxybenzaldehyde with 3,5-dimethoxybenzyl phosphonate in presence of sodium hydride yields 3,5-dimethoxy-4′-benzyloxystilbene; and debenzylating 3,5-dimethoxy-4′-benzyloxystilbene with aluminum chloride and N,N-dimethylaniline in dichloromethane yields Pterostilbene.
CN 1955153 discloses a process for preparing Pterostilbene by: condensing 3,5-Dimethoxybenzyl phosphonic acid diethyl esters with hydroxy benzaldehyde methoxymethyl ethers affords the substituted 3,5-Dimethoxy-4′-methoxymethyloxystyrylbenzene; and treating 3,5-Dimethoxy-4′-methoxymethyloxystyrylbenzene dissolved in methanol with Pyridinium p-toluene sulfonate (PPTS) yields Pterostilbene.
Indian Journal of Chemistry, Section B: 2002, 41B (11), 2395-2398 discloses a process for preparing Resveratrol by: treating Tri-O-methyl (—OMe) or tri-O-benzyl (—OCH2Ph) Resveratrol with BBr3 in CH2Cl2 yields Resveratrol.
U.S. Pat. No. 7,253,324 discloses a process for preparing Resveratrol by: treating Tri-O-methyl(—OMe) or tri-O-benzyl (—OCH2Ph) Resveratrol with AlCl3/N,N-dimethylaniline yields Resveratrol.
The limitations of the above methods are scalability and difficulty in selective deprotection to prepare Pterostilbene and use of expensive reagents for protection and/or low yields obtained in the process. So there is a need of the industry to have a process that is scalable and without using expensive reagents.
According to the present invention there is provided a convenient process for the preparation of stilbene with desired purity and yield by using a novel intermediate 3,5-Dialkyl-4′-O-tetrahydropyranylstilbene.
Both Resveratrol and Pterostilbene have been reported to exhibit a range of biological activities including anti-cancer, antioxidant, anti-inflammatory and other potential health benefits. Pterostilbene is found in nature in a variety of grapes and berries as well as plants commonly used in traditional folk medicine. Significant interest in Pterostilbene has been generated in recent years due to its perceived health benefits, leading to increased consumption of foods that contain the compound such as grapes and berries.
While limited solid-state characterization has been reported for Resveratrol, solid-state properties of Pterostilbene have not been thoroughly studied to date. The compound has been noted to have poor solubility in water, making it difficult to incorporate in food extracts or supplements (“nutraceuticals”) (Lopez-Nicolas, J. M.; Rodriguez-Bonilla, P.; Mendez-Cazorla, L.; Garcia-Carmona, F., Physicochemical Study of the Complexation of Pterostilbene by Natural and Modified Cyclodextrins, Journal of Agricultural and Food Chemistry 2009, 57, (12), 5294-5300.). In addition, Pterostilbene exhibits poor bioavailability and is easily oxidized by various enzymes (Pezet, R., Purification and characterization of a 32-kDa laccase-like stilbene oxidase produced by Botrytis cinerea, FEMS Microbiol. Lett. 1998, 167, 203-208, and Breuil, A. C.; Jeandet, P.; Adrian, M.; Chopin, F.; Pirio, N.; Meunier, P.; Bessis, R., Characterization of a pteristilbene dehydrodimer produced by laccase of Botrytis cinerea, Phytopathology 1999, 89, (298-302).). The melting point has been reported as 82° C. (Mallavadhani, U. V.; Sahu, G., Pterostilbene: A Highly Reliable Quality-Control Marker for the Ayurvedic Antidiabetic Plant ‘Bijasar’, Chromatographia 2003, 58, 307-312.) Efforts to improve the solubility of Pterostilbene have focused on formulation approaches such as by using cyclodextrins (Lopez-Nicolas 2009).
It is well established that solid-state properties of compounds can significantly affect their ability to become viable commercially such as by way of becoming an active pharmaceutical or nutraceutical ingredient in a formulated product. Properties, such as solubility, chemical stability, and physical stability, are known to vary, often significantly, between different solid forms of a compound.